Peptic ulcer such as gastric ulcer, duodenal ulcer and the like are resulted from the disruption of a balance between aggressive factors and protective factors. Examples of disruption-inducing factors include drugs (e.g., non-steroidal anti-inflammatory agents, adrenocortical hormone agents, antibiotics, anti-cancer agents, oral hypoglycemic agents), stress, alcohols, corrosive drugs, cirrhosis, anisakid spp., eating habits and the like. At present, aggressive factor inhibitors, protective factor enhancers, and combinations thereof are clinically used.
As the aggressive factor inhibitors, there are clinically used antacids (e.g., sodium bicarbonate and aluminum hydroxide gel, magnesium oxide etc.), anticholinergics (e.g., atropine sulfate, pirenzepine hydrochloride etc.), H2-receptor antagonists (e.g., cimetidine, ranitidine, famotidine, nizatidine, roxatidine etc.), proton pump inhibitors (e.g., omepurazor, ransoprazol, ransoprazol sodium etc.), anti-gastrin drugs (e.g., proglumide, secretin, urogastorone), and anti-pepsin drugs (sucrose sulfate ester, sucralfate etc.) and the like.
As the protective factor enhancers, there are clinically used mucosal protective drugs (e.g., sucralfate, rebamipide, teprenone etc.), mucosal covering drugs (e.g., sodium arginate, azunol preparation etc.), tissue repair accelerating drugs (e.g., aceglutamide aluminum, aldioxa, gefalnate etc.), mucus production accelerating drugs (e.g., proglumide, teprenone, secretin, aldioxa etc.), mucosal microcirculation improving drugs (e.g., cetraxate hydrochloride, benexate, sulpirid etc.), prostaglandin synthesis accelerating drugs (e.g., sofalcone) and prostaglandin preparations (e.g., ornoprostil, misoprostol, enprostil etc.) and the like. For chronic gastritis, digestive tract function improving drugs (e.g., cisapride, aclatonium napadisilate, bethanechol, domperidone, metoclopramide, trimebutine maleate) are also used.
Aggressive factor inhibitors, H2-receptor antagonists, proton pump inhibitors and the like are widely used because of having a potent gastric acid secretion-inhibiting activity and a prominent therapeutic effect. However, it has been revealed that there are high frequently a rebound of gastric acid secretion, and recurrence or exacerbation of ulcer when a drug administration is stopped even after completely cured once. Further, there were problems that there are ulcers which are not completely cured by a H2-receptor antagonist, and that hyperplasia of an enterochromaffin-like cell, hypergastrinemia, appearance of gastric carcinoid and the like are reported depending on use of a proton pump inhibitor and, thus, its dose is limited. While the protective factor enhancers have more mild actions as compared with the above aggressive factor inhibitors, their therapeutic effects were subsidiary. Therefore, patients having digestive organs disease and physicians have desired development of an aggressive factor inhibitor or a protective factor enhancer, which is neither a H2-receptor antagonist nor a proton pump inhibitor and can be safely and effectively used through other mechanism of action.
Meanwhile, it is known that PAR (protease-activated receptor) belongs to a seven-transmembrane type G protein coupling receptor, and is a receptor activated by a protease (Hollenberg, M. D., Trends Pharmacol. Sci., 17, 3-6, 1996 Hollenberg, M. D., Trends Pharmacol. Sci., 20, 271-273, 1999). PAR is cleaved by a protease at a specific N-terminal site of an extracellular domain, to expose a new N-terminus. It is believed that the newly exposed N-terminus becomes a chain ligand and is bound to its own activation site, whereby, activation of receptor is caused (Hollenberg, M. D., Trends Pharmacol. Sci., 17, 3-6, 1996 Hollenberg, M. D., Trends Pharmacol. Sci., 20, 271-273, 1999 Vu, T. K. et al., Cell, 64, 1057-68, 1991).
It is reported that subtypes of PAR-1, PAR-2, PAR-3, and PAR-4 exist in PAR, and that their functions differ from each another. It is found that PAR-1, PAR-3, and PAR-4 are activated by thrombin (Vu, T. K. et al., Cell, 64, 1057-1063, Hollenberg, M. D., Trends Pharmacol. Sci., 17, 3-6, 1996 Ishihara, H. et al., Nature, 386, 502-6, 1997 Kahn, M. L. et al., Nature, 394, 690-4, 1998 Xu, W. F. et al., Proc. Natl. Acad. Sci. USA, 95, 6642-6, 1998), and PAR-2 is activated by trypsin (Nystedt, S. et al., Proc. Natl. Acad. Sci. USA, 91, 9208-12, 1994 Molino, M. et al., J. Biol. Chem., 272, 6011-7, 1997) and tryptase (Molino, M. et al., J. Biol. Chem., 272, 6011-7, 1997 Fox, M. T. et al., FEBS Lett, 417, 267-9, 1997).
It is also known that there is a cleavage site on an amino acid sequence of the PAR-1 (Vu, T. K. et al., Cell, 64, 1057-1063, 1991), PAR-2 (Nystedt, S. et al., Proc. Natl. Acad. Sci. USA, 91, 9208-12, 1994), RAR-3 (Ishihara, H. et al., Nature, 386, 502-6, 1997) and PAR-4 (Kahn, M. L. et al., Nature, 394, 690-4, 1998 Xu, W. F. et al., Proc. Natl. Acad. Sci. USA, 95, 6642-6, 1998), and with respect to PAR-1, PAR-2 and PAR-4, the receptor is activated by exogenously adding a synthetic peptide consisting of five or six amino acids synthesized on the basis of an active amino acid sequence of a cleavage site (Vu, T. K. et al., Cell, 64, 1057-68, 1991 Nystedt, S. et al., Proc. Natl. Acad. Sci. USA, 91, 9208-12, 1994 Ishihara, H. et al., Nature, 386, 502-6, 1997 Kahn, M. L. et al., Nature, 394, 690-4, 1998 Xu, W. F. et al., Proc. Natl. Acad. Sci. USA, 95, 6642-6, 1998 Dery, O. et al., Am. J. Physiol., 274, C1429-52, 1998).
As one of the intracellular signals mediated by PAR-2, activation of inositol 1,4,5-triphosphate (IP3) and protein kinase C system are known (Hollenberg, M. D., Trends Pharmacol. Sci., 20, 271-273, 1999 Dery, O. et al., Am. J. Physiol., 274, C1429-52, 1998 Zheng, X. L. et al., J Pharmacol Exp Ther, 285, 325-34, 1998).
With respect to PAR-2, it is reported that there are inflammatory responses (Cirono, G. et al., J. Exp. Med., 183, 821-827, 1996 Kawabata, A et al., Br. J. Pharmacol., 125, 419-422, 1998), constricting and relaxing actions in trachea (Saifeddine, M. et al., Br. J. Pharmacol., 118, 521-531, 1996 Moffatt, J. D. et al., Br. J. Pharmacol., 125, 591-594, 1998 Cocks, T. M. et al., Nature, 398, 156-160, 1999 Hollenberg, M. D. et al., Can. J. Physiol. Pharmacol., 75, 832-884, 1997), and that PAR-2 is expressed in prostate gland, small intestine, colon, liver, kidney, and pancreas (Stephan, K. B. et al., Biochem. J., 341, 1009-1016, 1996).
However, there have not been reported to date on digestive organ system, such as a gastric acid secretion inhibiting action, a mucus secretion promoting action and a mucosal protecting action of PAR-2.